Many relatively simple surgical interventions still carry a significant risk of failure to heal or infection. Prevalence surveys suggest that approximately 8% of UK hospital patients have a healthcare-associated infection, with surgical site infections (SSIs) accounting for up to 20% of these (Plowman et al., J. Hospital Infection., 2001, 47:198-209). Nearly 5% of patients who had undergone a surgical procedure were found to have developed an SSI, with over one third of post-operative deaths resulting at least partly from SSIs. The cost of infection is significant, with an estimated 1-2 weeks' extra hospitalization for infected patients, a doubling of re-admission rates, and a tripling of overall healthcare costs.
Fournel et al., Brit. J. Surg., 2010, 97:1603-1613 published a meta-analysis of non-infected surgical sites, which underwent routine surgery with the benefit of gold standard aseptic surgical technique in pan-European centres. It was reported in this paper that surgical site infections were ubiquitous following routine and trauma surgery. Surgical site infection rates of 14% were the norm in the UK and France, whereas in Finland published figures suggest rates of up to 29% are commonplace. Surgical site infection rates of up to 40% have been reported for other countries.
The Fournel meta-analysis looked at the use of wound washes and found that four types were used during elective and trauma surgery:                1. Saline        2. Saline with bacitracin (a topical antibiotic)        3. Saline with chlorhexidine and povidone-iodine        4. Chlorhexidine povidone-iodine        
The current opinion among surgeons is that povidone-iodine application as a wound wash is beneficial and reduces rates of surgical site infection. Although the meta-analysis showed a statistically significant difference in surgical site infection rates when using povidone-iodine, the reduction observed was only from 14% to 8%.
Furthermore, generalised and local oedema (swelling) is frequently observed following major and simple surgery. This oedema is a product of inflammation, which originates at the surgical site, in part, as a result of the cytokine response to surgical injury. The oedema and inflammation is associated with clinical outcome, morbidity and mortality, such that a reduction in post-surgical inflammation and oedema would result in improved outcomes (Vaughan-Shaw et al., Ann. R. Coll. Surg. Eng., 2013, 95:390-396). In the Vaughan-Shaw (2013) study, death was more likely in those with post-operative oedema (47% vs 8%).
Furthermore, it is believed that specific proteins and molecules act as inflammatory mediators in the contribution to rheumatoid diseases (Montecucco et al., “Common Inflammatory mediators orchestrate pathophysiological processes in rheumatoid and arthritis,” Rheumatology, 2009, 48:11-22) as well as Alzheimer's degenerative disorders of the nervous system (Akiyama et al. Inflammation and Alzheimer's disease. Neurobiology of aging. 2000; 21:383-421). The ability to modify or attenuate the bio-activity of these mediators would impact the progression of these diseases.
A dental extraction/oral surgical procedure is analogous to the intentional creation of a compound fracture in the oral cavity, where the wound is left to heal by secondary intention. Although osteomyelitis (infection) is rare after any oral and maxillofacial surgery, alveolar osteitis (AO) is a well-recognised post-surgical inflammatory disorder, which is easily diagnosed and simply recorded as a clinical outcome. AO is an inflammatory condition of failed healing, where the clot disintegrates and the lining of the alveolar bone becomes inflamed and painful. The incidence of AO following dental-oral surgical procedures is reported to be within the range of 5-40% (recent reports are consistently in the 22-30% range). This is similar to rates of delayed, difficult or painful healing reported for other surgical sites.
In 2012 both Tolstunov et al., Brit. Dent. J., 2012, 213(12):597-601 and Yengopal et al., Int. J. Oral Maxillofac. Surg., 2012, 41:1253-1264 reported on AO and current methods used to reduce its incidence. Neither report found evidence of effectiveness using chlorhexidine (0.2% solution or gel) or isotonic (normal) saline surgical site irrigation. Indeed, the most startling finding was that doing nothing was preferable to using any surgical site treatment, which is consistent with the understanding that AO is inflammatory in aetiology and not a response to infection.
Leg ulcers, particularly venous leg ulcers, are chronic wounds and inflammatory lesions, which often require lengthy treatment periods to heal or are difficult to heal at all. Venous ulcers are estimated to affect approximately one million people per year in Europe, and half a million people per year in the USA. The condition is particularly prevalent in older people, with the UK National Health Service estimating that 1 in 50 people over the age of 80 develop venous leg ulcers. The economic impact of hard to heal ulcers has been provided by Rippon et al., Wounds, UK, 2007, 3(2):58-69. Current recommended treatments are compression treatment or simple wound dressing, but there remains a need for a cheap, effective treatment, which can aid the healing of non-healing or difficult to heal leg ulcers.
Thus there continues to be a need for effective means to reduce the incidence rates of non-healing wounds and other inflammatory disorders following surgical intervention.
Recent reviews, studies, and definitive opinions from Cochrane library reviews and meta-analyses describe best practice in routine wound care and care for non-infected wounds, infected wounds and non-healing wounds (M. L. Rotter, “Special problems in hospital antisepsis,” in Russell, Hugo & Aycliffe's Principles and Practice of Disinfection, Preservation & Sterilisation, 4th Ed. Blackwell Pub. 2008, Ch. 17: 540-562; Damour et al., Burns, 1992, 18(6):479-485; Fournel et al., Brit. J. Surg., 2010, 97:1603-1613; Brolmann et al., Brit. J. Surg., 2012, 99:1172-1183; Atiyeh et al., Int. Wound J., 2009, 6:420-430; Walter et al., Brit. J. Surg., 2012, 99:1185-1194; Thomas et al., J. Trauma, 2009, 66:82-91).
The present gold standard for the treatment with irrigation or cleansing of wounds is sterile saline or sterile water, usually in conjunction with antibiotics for the routine treatment of non-infected wounds. Pre-operative site preparations are used as topical antimicrobial agents before surgery. The use of antiseptics is not recommended in this context (Atiyeh et al., Int. Wound J. 2009, 6: 420-430; Fournel et al., Brit. J. Surg., 2010; Brolmann et al., Brit. J. Surg., 2012, 99:1172-1183; Leaper, Br. J. Surg., 2010, 97:1601-1602; Walter et al., Brit. J. Surg., 2012, 99:1185-1194).
Current best practice advises against the use of aqueous chlorine on wounds except for on infected wounds and where other treatment modalities have failed (Vissers et al., Biochem. J., 1999, 334:443-449; M. L. Rotter, “Special problems in hospital antisepsis,” in Russell, Hugo & Aycliffe's Principles and Practice of Disinfection, Preservation & Sterilisation, 4th Ed. Blackwell Pub., 2008, Ch. 17:540-562; Damour et al., Burns, 1992, 18(6):479-485; Fournel et al.,Brit. J. Surg., 2010; Brolmann et al., Brit. J. Surg., 2012, 99:1172-1183; Walter et al., Brit. J. Surg., 2012, 99:1185-1194; and Atiyeh et al., Int. Wound J., 2009, 6:420-430).
Prior to the introduction of antibiotic chemotherapy, there was interest in the use of antiseptics for all wounds. Aqueous chlorine was assessed along with many other antiseptics, which were originally selected for their antimicrobial action. However, any interest in aqueous chlorine for use on all but infected, contaminated or chronic, non-healing wounds was ended by the seminal cytotoxicity study of Kozol et al., Arch. Surg., 1988, 123:420-423 and condemnation by Lineweaver et al., Arch. Surg., 1985, 120:267-270; and Leaper, Br. Med. J., 1992, 304:930-931). Subsequent investigations have shown that the benefits of the antimicrobial action of aqueous chlorine are outweighed by the harmful effects and cytotoxicity (Brennan et al., Brit. J. Surg., 1985, 72:780-782; (Vissers et al., Biochem. J., 1999, 334:443-449; Hideago et al., J. Burn Care Rehabil., 1991, 12:265-268; and Thomas et al., J. Trauma, 2009, 66:82-91; Coetzee et al., J. Burns, 2012, 38:529-533).
The rationale used by all advocates, whether current or historical, for the use of aqueous chlorine has been its antimicrobial action. Furthermore, all advice against the use of aqueous chlorine centres on its cytotoxicity.
Furthermore, while the use of aqueous chlorine in healthcare has been described in the context of the disinfection of surfaces and of contaminated wounds [see, for example, Bashford et al., Lancet, 1917, 2:595-597; Bunyan, Brit. Med. J., 1941, 4002-4007; and Century Pharmaceuticals Inc., Dakin's solutions product information and material safety data sheet, 2011, www dot dakins dot net slash index dot html], any such use has been limited by the prevailing knowledge that toxicity is a problem associated with the use of aqueous chlorine in the treatment of contaminated wounds.
Investigators have demonstrated that the toxicity seen and reported are such that only dilute solutions may be applied to live human or animal tissues without adverse effect. This reduction in concentration reduces antimicrobial efficacy, which is the only function of the aqueous chlorine solution in healthcare that has been reported to date.
Where the literature describes the use of aqueous chlorine solutions as anti-microbial and disinfectant agents, it is generally as a low pH solution to maximise the levels of hypochlorous acid, which is known to be an effective anti-microbial (see, for example, Chang, Journal of American Water Works Association, 1944, 36:1192-1207). Where the pH of the aqueous chlorine solution is not deliberately kept low, such formulations use a buffer to maintain a higher pH and maximise stability of the solution (see, for example, Estrela et al., J. Appl. Oral Sci., 2008, 16(6):364-368).
In recognition of the potential toxicity of hypochlorous acid alternative, less reactive antimicrobial agent alternatives have been developed to treat chronic non-healing and infected wounds, e.g., an N-Chloramine compound (NVC-422) developed by Novabay Pharmaceuticals. These alternative antimicrobial agents have been developed to address the cytotoxicity of aqueous chlorine, which is described as causing cellular damage and pain (see, for example, Gottardi et al., Antimicrob. Agents Chemother., 2013, 57(3):1107).
While the concept of using anti-microbial agents to wash out surgical sites has recently been discussed in the literature, the only antiseptic agents which were considered to be safe to use to wash out surgical sites and wounds were chlorhexidine 0.2% and povidone-iodine (see, for example, Khan et al., J. Tissue Viability, 2006, 16:6-10; Kozol et al., Arch. Surg., 1988, 123:420-423), refs. 28-30; and Leaper, Br. Med. J., 1992, 304:930-931).
In the seminal Kozol et al paper on the use of hypochlorite in a wound discussed earlier, it was concluded that, “there is no concentration at which it is safe to use hypochlorite on a wound.” This statement has become the accepted knowledge of healthcare professionals and permeates wound-care policy.
The inventor of the present invention has now surprisingly found that that the aqueous hypochlorite solution according to the present invention is very beneficial in reducing the healing time and reducing the associated problems found with the healing of non-infected and uncontaminated surgical sites.
It has further been found that the aqueous hypochlorite solution of the present invention brings about the resolution of inflammatory disorders of the skin, mucosa and other surfaces, e.g., mouth ulcers, eczema, psoriasis, and leg ulcers, such as venous leg ulcers, where the cause is not microbial or infection.
Current treatment methods include skin moisturising with non-irritant emollients, compression treatment (in the case of leg ulcers), topical corticosteroid use, systemic corticosteroid medication (for severe acute episodes) and, in severe cases, systemic immunosuppressive therapy. All of these treatments have their limitations: emollients do not impact the inflammatory process and do not counter secondary infection; topical corticosteroids suppress cellular mediated immune responses, can compound the tendency to secondary infection and produce atrophy of the treated skin; and systemic immunosuppressive therapy has been linked to an increase in cancer incidence. As a result of these limitations many patients self-manage lesions over many months and often years.
It has further been found that use of an aqueous hypochlorite solution as a wound irrigant reduces the incidence of alveolar osteitis (AO) following dental-oral surgical procedures.
The beneficial effects of the solution of the present invention is particularly surprising because all literature to date has stated that the only safe use of hypochlorite solutions on wounds is to reduce a microbial bio-burden and treat infection.
It has surprisingly been found that a specific hypochlorite solution has a novel action on the inflammatory response and healing process associated with uncontaminated and non-infected surgical sites and wounds, as well as trauma sites and surface inflammatory lesions where there is no infection, e.g., recurrent oral ulcers, allergic dermatitis/eczema, psoriasis, and leg ulcers, such as venous leg ulcers.